This career development application has two components: I. A mentored research project, and II. Educational/training activities. Epidemiological studies have implicated intestinal inflammation and chronic activation of the immune system in the etiology of IBS for some patients. Recent research in animal models suggests that these factors can be involved in the pathophysiological mechanisms responsible for intestinal dysmotility and visceral hypersensitivity. However, the role of intestinal inflammation and mucosal immune activation has not been adequately and systematically investigated in patients with IBS. In the proposed research project we will compare sub-clinical mucosal inflammation between patients with diarrhea predominant IBS (D-IBS) and control. We will specifically look at pro- and anti-inflammatory cytokines and inflammatory-associated neuropeptides. Analyses will be performed by Real-time PCR and ELISA techniques to verify results. In our second aim we will investigate whether alterations in inflammatory markers are associated with alterations with relevant intestinal physiology including colonic pain thresholds, phasic motility, and smooth muscle tone. We will study 33 IBS patients with D-IBS and 33 healthy controls. Intestinal physiological data will be collected on the same study population of an NIH supported study on the heterogeneity of IBS (NIDDK Grant DK 31369, Whitehead PI) on which Dr. Whitehead is collaborating with Dr. Ringel. The educational/training components of this proposal have been developed with the advice of Dr. Ringel's mentors: Dr. Balfour Sartor is a world renowned expert and researcher in intestinal inflammation and Dr. William Whitehead is a world renowned expert and researcher in functional Gl disorders. We propose formal coursework as well as laboratory training aiming to expand and increase Dr. Ringel's knowledge and skills in theories and research methodologies in these areas. The overall goal is to establish Dr. Ringel as an independently-funded translational researcher. Thus, the methodologies, results and protocols that will be developed during the award will be used to design mechanistic intervention studies and as preliminary data for submission of future (NIH) grants.